Given the variable clinical presentation and imaging findings with potential for the rapid development of respiratory failure, a high index of suspicion for pneumonitis should be maintained in patients on ICI therapy who develop respiratory symptoms. Annual Review of Cancer Biology Vol. If there is no response within 3 to 5 days, infliximab should be considered; a single 5‐mg/kg dose is usually sufficient.9, 11 In a retrospective series that included 75 patients who had immune‐related enterocolitis, infliximab use was associated with a shorter time to symptom resolution and shorter duration of steroid use, and there was no decrease in overall survival.43 In another retrospective series, which included 117 patients treated with ICI who developed diarrhea, a steroid duration >30 days was associated with higher rates of infection compared with a shorter duration of steroid use with or without infliximab.44 In a retrospective series of the endoscopic and histologic features of ICI‐induced colitis, patients with ulcerations on colonoscopy were more likely to have steroid‐refractory colitis.45, Vedolizumab, an anti‐integrin α4β7 antibody with gut‐specific effects, has been investigated for patients with steroid‐dependent or refractory ICI‐induced colitis. Review Current status and future directions of cancer immunotherapy Hongming Zhang, Jibei Chen Department of Respiratory Medicine, Yancheng Third People's Hospital, the Affiliated Yancheng Hospital of Southeast University Medical College, Yancheng, Jiangsu, China. First, neurotoxicity may arise from the diffusion of cytokines into the CNS. Guillain‐Barre syndrome and noninfectious meningitis were more common with anti–CTLA‐4 compared with anti–PD‐1/anti–PD‐L1 therapy and with combination therapy compared with monotherapy. The differential diagnosis of acute kidney injury in patients receiving ICI therapy includes dehydration, sepsis, and other medications. There was no improvement in the recovery of pituitary function noted with higher doses of steroids. The diversity of these mutations and phenotypes presents a challenge to the development of drugs that target p53 mutant cancer ...Read More. Eight patients discontinued treatment, and there were no treatment‐related deaths. This characteristic finding of an awake patient who is mute and unable to follow commands can help distinguish ICANS from other causes of encephalopathy. Therapeutic Advances in Gastroenterology 2020 10.1177/1756284820917527 Download Citation. Cancer immunotherapies, which were developed based on studies of the mechanisms of tumor escape, manipulate the immune system to reactivate the antitumor immune response and overcome the pathways leading to escape. Neurologic toxicity has been reported in clinical trials of multiple immune effector cell therapies, including CD19 CAR‐T cells, CAR‐T cells targeted to non‐CD19 antigens, and bispecific antibody therapy.112, 118, 124, 125 In a phase 1 study of 53 adult patients who received CD19 CAR‐T cells for B‐ALL, grade 1 and 2 neurotoxicity was observed in 11 patients, and grade 3 and 4 neurotoxicity was observed in 22 patients.121 The incidence of neurotoxicity resulting from CAR‐T cells specific for solid tumor antigens is less well characterized and may vary based on the specific target antigen. An autopsy series of 6 patients treated with CTLA‐4 blockade, which included patients with and without hypophysitis, found that CTLA‐4 was expressed by pituitary cells in all patients at different levels, with the highest level of CTLA‐4 expression noted in a patient with severe hypophysitis, suggesting that the administration of anti–CTLA‐4 antibodies to patients with high levels of pituitary CTLA‐4 expression may lead to severe hypophysitis.19 The pathophysiology of thyroid dysfunction associated with PD‐1 blockade is incompletely understood, although a study of patients with advanced non–small cell lung cancer (NSCLC) treated with pembrolizumab found that antithyroid antibodies were present in 80% of patients who developed hypothyroidism compared with 8% of patients who did not, suggesting that anti–PD‐1 antibodies may modulate humoral immunity.20 Studies have suggested that irAEs may develop through the targeting of antigens shared by normal and tumor tissue. Pittsburgh, PA: Oncology Nursing Society; 2019:149-189. Division of Medical Oncology, Duke University, Durham, North Carolina. The difference in the incidence of hypophysitis with ipilimumab versus tremelimumab is hypothesized to be because of their different immunologic subclasses. 7, 8 Cancer immunotherapy was generally ignored until the middle of the last century, when chemically induced tumors of inbred mice were found to elicit predictable transplantation resistance, and “spontaneous” regressions of several human solid tumors suggested that tumor regression might be achieved using emerging new immunological approaches. IL‐17 is a cytokine that is upregulated in inflammatory bowel disease,16 and a study of patients with melanoma treated with neoadjuvant ipilimumab found that baseline serum IL‐17 levels were correlated with the development of grade 3 diarrhea or colitis.17 Studies have examined the role of pituitary CTLA‐4 expression in the development of hypophysitis.18, 19 In a series of 7 patients with ipilimumab‐induced hypophysitis, pituitary antibodies were negative at baseline but developed in all 7 patients, predominantly against thyroid‐stimulating hormone (TSH)–secreting cells, although some patients also developed antibodies against follicle‐stimulating hormone–secreting or adrenocorticotropic hormone (ACTH)–secreting cells.18 These antibodies led to defects in the associated hormone axis. The variation in the rate of irAEs with rechallenge observed in these 2 studies may reflect differences in the initial immunotherapy leading to irAE, because patients in the study by Pollack et al transitioned from combination therapy to anti–PD‐1 monotherapy, which has a lower overall toxicity profile, whereas many of the patients in the study by Simonaggio et al developed the initial irAE on anti–PD‐/1PD‐L1 monotherapy and were later rechallenged with the same class of therapy. Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States, with an estimated 135 430 new cases and 50 260 cancer-related deaths annually (1). A retrospective series including 45 patients who developed thyroid dysfunction after either anti–PD‐1 monotherapy or combination anti–PD‐1/anti–CTLA‐4 therapy for multiple tumor types found that 22% of patients initially presented with hypothyroidism, and the remaining 78% initially presented with thyrotoxicosis.63 Of the patients with thyrotoxicosis, 80% later developed hypothyroidism. Here the authors describe the roles of dendritic cells in the tumour … For example, CHECKMATE 016 (Nivolumab [BMS‐936558; MDX‐1106] in Combination With Suntinib, Pazopanaib, or Ipilimumab in Subjects With Metastatic Renal Cell Carcinoma [RCC]) evaluated the safety and efficacy of different regimens of ipilimumab‐nivolumab, including nivolumab at a dose of 3 mg/kg and ipilimumab at a dose of 1 mg/kg (N3I1), nivolumab at a dose of 1 mg/kg and ipilimumab at a dose of 3 mg/kg (N1I3), and nivolumab at a dose of 3 mg/kg and ipilimumab at a dose of 3 mg/kg (N3I3), for metastatic RCC (mRCC).53 In the N1I3 arm, 21% of patients developed grade 3 and 4 elevation in aspartate and alanine aminotransferase (AST/ALT) levels compared with a 4% incidence of grade 3 AST/ALT elevation in the N3I1 arm. Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. If adrenal insufficiency and hypothyroidism are both present, steroids should be started before thyroid hormone replacement to prevent adrenal crisis.11 Patients with adrenal insufficiency should be educated about the potential life‐threatening nature of adrenal crisis and should be provided with stress doses of hydrocortisone in case of infection, trauma, or illness.11. The most exciting paradigm change in cancer treatment in recent years, however, has been immunotherapy. The incidence of any‐grade irAE in trials including patients with multiple solid tumor types has been reported at 72% with ipilimumab monotherapy25 and 66% with anti–PD‐1/anti–PD‐L1 monotherapy.26 The incidence of irAEs is higher with combined PD‐1 and CTLA‐4 blockade.27, 28 A meta‐analysis of fatal irAEs in patients treated with PD‐1, CTLA‐4, or combined blockade reported toxicity‐related fatality rates of 0.36% with anti–PD‐1, 0.38% with anti–PD‐L1, 1.08% with anti–CTLA‐4, and 1.23% with combined anti–PD‐1/anti–PD‐L1 and CTLA‐4.29 The type of fatal irAE observed varied by regimen, with death most often resulting from colitis (70%) with anti–CTLA‐4 therapy, compared with pneumonitis (35%), hepatitis (22%), or neurotoxicity (15%) with anti–PD‐1/anti–PD‐L1 therapy. 3:55-75 (Volume publication date March 2019) First published as a Review in Advance on November 7, 2018 https://doi.org/10.1146/annurev-cancerbio-030518-055552 The median onset of moderate to severe endocrine irAEs in patients with melanoma who are treated with ipilimumab occurs at 7 to 20 weeks.60 A single‐institution retrospective review including 256 patients with melanoma who received ipilimumab reported a median time to onset of hypophysitis of 4 months; however, the timing was variable, ranging from 8 to 19 months after initiation of therapy.61 The timing of hypothyroidism was also variable, with presentation occurring within the first 5 months and up to 3 years after the initiation of therapy.61 A pooled analysis of safety events in patients with melanoma who received nivolumab reported a median time to onset of approximately 10 weeks.62. Toxicity can affect nearly any organ system, and multiple presentations of rare but severe irAEs have been reported, highlighting the importance of vigilant monitoring and multidisciplinary collaboration. In severe cases, this can result in multiorgan failure, which has historically limited the clinical utility of cytokine therapy.6 ICIs, including antibodies against cytotoxic T lymphocyte antigen‐4 (CTLA‐4) and programmed cell death protein 1 (PD‐1) and its ligand PD‐L1, disinhibit T‐cell antitumor function, which can lead to a distinct constellation of organ‐specific inflammatory side effects, or irAEs.5 Another approach to immunotherapy is the ex vivo modification of patient T cells to generate specific antitumor reactivity, a process termed adoptive cell therapy.7 For instance, chimeric antigen receptor (CAR) T cells, which are engineered to recognize a tumor‐associated antigen, are used to treat hematologic malignancies and are being investigated in multiple solid tumor types.7 The most common CAR‐T toxicities in hematologic malignancies are cytokine release syndrome (CRS) and ICANS.8 Because of these toxicity profiles, treatment with cancer immunotherapies requires close monitoring, and toxicity often requires specific management, which can include steroids or immune‐modulating agents.5 As the use of immunotherapy in cancer continues to expand, guidelines addressing the management of ICI and CAR‐T toxicity have also been developed.5, 9-11. Figure 1: Moving beyond checkpoint blockade to enhance antitumor immunity. Revised 12 Feb 2018. ICANS may present with a diverse range of neurologic symptoms; however, patients often develop a characteristic evolution of neurologic features.111 Patients initially develop tremor, dysgraphia, mild expressive aphasia, apraxia, and impaired attention. First published as a Review in Advance on November 7, 2018 Nature. Authors submitting to the journal receive a first … Yang F, Markovic SN, Molina JR, Halfdanarson TR, Pagliaro LC, Chintakuntlawar AV, et al. Association of sex, age, and eastern cooperative oncology group performance status with survival benefit of cancer immunotherapy in randomized clinical trials: a systematic review and meta-analysis. Yet only recently has this powerful strategy finally taken center stage in mainstream oncology. The incidence of irAEs with single‐agent ICI varies by agent, tumor type, and disease setting. Retrospective studies have examined outcomes in patients who received earlier treatment with biologic agents. and you may need to create a new Wiley Online Library account. In Olsen MM, LeFebvre KB, Brassil KJ, eds. Cao et al. Cancer Research Institute. Ganoderma: A Cancer Immunotherapy Review κ B (I κ B) kinase and nuclear factor (NF)- κ B inhibitors, as well as the phosphorylation of I κ B α and p38 mitogen- These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. 3, 2019, Blocking antibodies to the immune checkpoint receptors or their ligands have revolutionized the treatment of diverse malignancies. Different CAR‐T manufacturing techniques may lead to variable safety and efficacy profiles. Metrics details. Overcoming hurdles in cancer immunotherapy. Infliximab is contraindicated according to some guidelines given concerns about hepatotoxicity5, 9, 10; however, a case report describing the use of infliximab in a case of life‐threatening hepatitis refractory to high‐dose steroids and mycophenolate mofetil in a patient who received ipilimumab‐nivolumab for metastatic melanoma has been published.56 The patient received 2 cycles of infliximab at a dose of 5 mg/kg 2 weeks apart with a partial response achieved; there were no identifiable hepatic AEs resulting from infliximab. A meta‐analysis including 38 randomized clinical trials compared the incidence of endocrinopathies resulting from different regimens and found that the incidence of hypophysitis was highest in patients who received ipilimumab and that the incidence of thyroid dysfunction was more common with anti–PD‐1 monotherapy than with anti–CTLA‐4 monotherapy.58 Other endocrinopathies, including primary adrenal insufficiency and insulin‐dependent diabetes mellitus, are rare and were reported in 0.7% and 0.2% of patients, respectively.58 A similar meta‐analysis including 101 clinical trials of patients with multiple solid tumor types reported a pooled 5.6% incidence of hypophysitis in patients treated with ipilimumab.59 The incidence of hypophysitis with tremelimumab, the other CTLA‐4 therapy investigated, was lower (1.8%). We carried out a systematic review of IAD cases induced by cancer immunotherapy published to date using PubMed’s database. depending on the type of immunotherapy and are related to the specific mecha-nism of action. In the era of the rapid development of cancer immunotherapy, there is a high level of … Received 25 Oct 2017. A team of researchers has found disrupting the interaction between cancer cells and certain immune cells is more effective at killing cancer cells than current immunotherapy treatments. Clinical trials continue to expand the indications for these therapies and to explore new methods of harnessing the immune system to treat cancer. A high index of suspicion should be maintained for rheumatologic toxicity in patients with acute musculoskeletal symptoms, as erosion and irreversible joint damage can occur within weeks.11 Grade 1 toxicity is managed with nonsteroidal anti‐inflammatory drugs, followed by prednisone if no improvement occurs. The cornerstone of toxicity management is often steroids or immunosuppression, and ongoing studies are evaluating the effect of immunosuppression on antitumor efficacy. The successful use of antithymocyte globulin has been reported for a case of steroid‐refractory hepatitis and can be considered in cases of acute clinical deterioration.57, Endocrinopathies associated with ICI include hypothyroidsm or hyperthyroidism, thyroiditis, hypophysitis, primary adrenal insufficiency, and insulin‐dependent diabetes mellitus.58 The pattern of endocrinopathy varies by agent, with the highest incidence after combination therapy. Received 25 Oct 2017. Immunotherapy. Illustration of key pathways and processes relevant to the initiation and execution of ferroptosis. It also uses cookies for the purposes of performance measurement. Ganoderma, also called Lingzhi, is one of the most well-known medicinal species. In patients with preexisting autoimmune disease or a history of prior irAEs, there is a risk of exacerbation of autoimmunity, redevelopment of prior irAEs, or development of de novo irAEs with ICI therapy. Adrenal insufficiency secondary to ICI‐induced hypophysitis is usually permanent and requires lifelong hormone replacement.71 Recovery of secondary hypothyroidism and hypogonadism has been described with frequency varying from 6% to 64% and 11% to 57%, respectively.71 A retrospective study of 25 patients with advanced melanoma and ipilimumab‐induced hypophysitis found that high‐dose steroid treatment did not improve the frequency of resolution or the time to resolution of hypophysitis.73 A large retrospective series including 98 patients with melanoma and ipilimumab‐induced hypophysitis examined the effect of glucocorticoid dose on survival and found that patients who received low‐dose glucocorticoids (maximum average daily dose, 7.5 mg of prednisone during the first 2 months after diagnosis) had longer overall survival and time to treatment failure compared with patients who received higher doses of glucocorticoids.74 These differences remained when adjusted for other prognostic factors, including performance status and lactate dehydrogenase levels. The two main drivers behind this success are checkpoint inhibitors (CPIs) and chimeric antigen receptor (CAR) T cells. Abstract. Two sessions of the conference were focused on clinical updates of ICIs. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ASTCT, American Society for Transplantation and Cellular Therapy; CBC, complete blood count; CMP, comprehensive metabolic panel; CRP, C‐reactive protein; CRS, cytokine release syndrome; EEG, electroencephalogram; HLH/MAS, hemophagocytic lymphohistiocytosis/macrophage activation syndrome; ICANS, immune effector cell‐associated neurotoxicity syndrome; ICE, immune effector cell‐associated encephalopathy; ICP, intracranial pressure; MRI, magnetic resonance imaging. 1 Department of Biological Sciences, Faculty of Science, Egerton University, P.O. PD‐1 is a cell‐surface receptor expressed on multiple immune cell types, including T cells, B cells, and NK cells, and binds to the ligands PD‐L1 and PD‐L2.5 PD‐L1 is expressed on multiple tissue types, including tumor cells, whereas PD‐L2 is expressed primarily on hematopoietic cells. Workup includes urinalysis and renal ultrasound. Cancer treatment vaccines are a type of immunotherapy that treats cancer by strengthening the body’s natural defenses against the cancer. Nevertheless, in the last few years, CD40 mAbs have begun to show efficacy, particularly in combination with other therapies, and are now seen as a potentially important and as yet untapped mechanism to extend the effective range of current cancer immunotherapy to include tumors in which baseline T cell activation is insufficient. Patients with grade ≥2 CRS should be treated with tocilizumab at a dose of 8 mg/kg intravenously for a maximum of 4 doses; steroids should be added in cases of grade 3 and 4 toxicity and in cases of grade 2 toxicity with persistent hypotension after anti–IL‐6 therapy.5, Tocilizumab is an IL‐6 receptor antagonist that has been shown to lead to rapid resolution of CAR‐T–induced CRS116 and is FDA‐approved for the treatment of severe CRS based on a retrospective analysis of 45 patients (median age, 12 years) who were treated with CD19 CAR‐T cells and received tocilizumab for CRS; the response rate was 69%.117, The ideal timing of tocilizumab, including the benefit of early use in patients at high risk and the effect of steroids and tocilizumab on the durability of remission, are subjects of ongoing study. The growing clinical application of immunotherapy highlights the importance of the recognition and management of its unique toxicity profile. The objective of this review is to describe the current status of immunotherapy in breast cancer, highlighting its potential in both early-stage and metastatic disease. Some tumor cells survive elimination and enter the equilibrium phase, during which the adaptive immune system prevents outright tumor growth but exerts a selective pressure on the remaining malignant clones. Advances in immunotherapy for colorectal cancer: a review. Anna Meiliana, Nurrani Mustika Dewi, Andi Wijaya. The available retrospective data suggest that earlier initiation of biologic therapy may lead to a reduction in steroid use and improved colitis‐related outcomes with similar oncologic outcomes. Figure 3: Challenges to studying metabolic heterogeneity. For example, an analysis of neurologic adverse events in 133 adults who received CD19 CAR‐T cells for multiple types of hematologic malignancies found that neurotoxicity was more common in younger patients, patients with B‐ALL, those with high tumor burden, and those who received a high CAR‐T cell dose.123 A higher CAR‐T dose was also associated with the development of more severe neurotoxicity. These include cellular therapies to bypass endogenous immunity and efforts to stimulate new adaptive antitumor responses using vaccines, adjuvants, and combinations with cytotoxic therapy, as well as strategies to inhibit innate immune suppression and modulate metabolism within the tumor microenvironment. Higher serum levels of IL‐15, IL‐6, IL‐10, and IP‐10 have been described in patients who develop high‐grade neurotoxicity.126 Second, trafficking of CAR‐T cells into the CNS may lead to the development of neurotoxicity. Around 100 patients a year in England will be among the first in the world to get cutting-edge cancer treatment on the NHS after regulators approved the use of a new immunotherapy treatment. A case series that included 3 patients with metastatic melanoma who developed severe polyarthritis secondary to ICI therapy described significant clinical improvement in all 3 patients in addition to durable antitumor response in 1 of 3 patients after treatment with tocilizumab.80. Immune cells in the tumor microenvironment have an important role in regulating tumor progression. 48 Ledford H: Cocktails for cancer with a measure of immunotherapy. CRP, ferritin, and other markers of inflammation, including IFN‐γ, IL‐6, and IL‐10, are elevated in patients with CRS.109, 112, 113 Patients with grade 1 CRS should be treated with broad‐spectrum antibiotics along with other workup and supportive care, depending on the end‐organ toxicities observed. Cancer immunotherapy, leveraging the host's coordinated immune system to fight against tumor has been clinically validated. PD‐1 signaling inhibits previously activated T cells in peripheral tissues.12 CTLA‐4 and PD‐1 signaling are tightly regulated to permit self‐tolerance; however, tumor cells can use these pathways, including checkpoint protein signaling, to evade the immune response and establish a microenvironment that permits tumor growth.2, 3, 13 Upregulation of the PD‐1 pathway by tumor cells can promote the development of T‐cell exhaustion, characterized by reduced T‐cell effector function and proliferation.12. Brodsky AN. For instance, a meta‐analysis that included 20 trials of anti–PD‐1 therapy for melanoma, NSCLC, and RCC found that the incidence of all‐grade and grade ≥3 pneumonitis was higher in patients who had NSCLC (4.1% and 1.8%, respectively) compared with those who had melanoma (1.6% and 0.2%, respectively). Annual Review of Cancer Biology Metabolism in the Tumor Microenvironment Allison N. Lau and Matthew G. Vander Heiden Annual Review of Cancer Biology CAR T Cell Therapy for Solid Tumors Kheng Newick, Shaun O'Brien, Edmund Moon, and Steven M. Albelda … Cancer immunotherapy—the science of mobilizing the immune system to kill cancer—has been pursued for more than a century. The presentation of cardiac irAEs varies and can include dyspnea, chest pain, or acute cardiovascular collapse.11 Cardiac irAEs include myocarditis, pericarditis, cardiac fibrosis, arrhythmias, and new‐onset heart failure.11 Myocarditis can be rapidly fatal; in the multicenter registry of patients with ICI‐induced myocarditis, 16 of 35 patients with myocarditis experienced a major adverse cardiac event at a median follow‐up of 102 days, including 6 cases of cardiovascular death, 3 of cardiogenic shock, 4 of cardiac arrest, and 3 of complete heart block,94 highlighting the potentially life‐threatening nature of this irAE and the importance of vigilant monitoring. Noninfectious encephalitis/myelitis was more common with anti–PD‐1/anti–PD‐L1 therapy than with anti–CTLA‐4 therapy and with combination therapy versus monotherapy. Abstract. Learn more. Clinical trials of adult and pediatric patients with various hematologic malignancies who are treated with CD19 CAR‐T have a reported variable incidence of CRS, with the incidence of any‐grade CRS ranging from 35% to 100% and severe CRS ranging from 1% to 28%.109 The reported incidence and severity vary between trials; however, comparison between trials is limited by different patient populations, malignancies, CAR‐T products, and CRS grading systems. View Article: Google Scholar: PubMed/NCBI. Thirty‐two of 43 observed neurologic events were grade 3 or 4, and 1 case of encephalitis was fatal. Grade ≥3 elevation in AST, ALT, or bilirubin, Presence of hemophagocytosis in bone marrow or other organs, Grade is assigned based on the most severe event that is not attributable to another cause. Academic Editor: Célia Cabral. Recent updates in cancer immunotherapy: a comprehensive review and perspective of the 2018 China Cancer Immunotherapy Workshop in Beijing. Box 536-20115, Egerton, Kenya. CII is keen to publish broad-ranging ideas and reviews, results which extend or challenge established paradigms, as … Figure 1: Compounds that induce ferroptosis. Patients who develop hypothyroidism should be treated with thyroid hormone replacement after adrenal insufficiency has been ruled out.5, 9-11 Thyroiditis should be managed conservatively during the thyrotoxic phase; however, other causes of thyrotoxicosis, including Graves disease, should be ruled out with laboratory tests, imaging, and endocrinology referral. Immunotherapy is a type of cancer treatment that helps your immune system fight cancer. Because the currently available data do not show that high‐dose steroids lead to improved recovery of pituitary function, guidelines recommend careful consideration of the risks and benefits of high‐dose steroids.10 Patients with headache, compressive symptoms, or adrenal crisis should be treated with methylprednisolone or prednisone at a dose of 1 to 2 mg/kg daily until symptom resolution5; however, patients without these symptoms can be managed with physiologic replacement doses. Immunotherapy has become a powerful clinical strategy for treating cancer. Concurrent severe AEs are common in patients with cardiac irAEs and occurred in 42 of 101 patients with myocarditis, most commonly myositis (25 patients) and myasthenia gravis (11 patients).95. This review will focus on the existing data for immunotherapy in SCLC, including immune checkpoint inhibition and exploring correlated emerging biomarkers.
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